EP3052128A2 - Tweak-antagonisten zur behandlung von lupus nephritis und muskelatrophie - Google Patents

Tweak-antagonisten zur behandlung von lupus nephritis und muskelatrophie

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Publication number
EP3052128A2
EP3052128A2 EP14790424.7A EP14790424A EP3052128A2 EP 3052128 A2 EP3052128 A2 EP 3052128A2 EP 14790424 A EP14790424 A EP 14790424A EP 3052128 A2 EP3052128 A2 EP 3052128A2
Authority
EP
European Patent Office
Prior art keywords
seq
tweak
tweak antibody
amino acid
antibody
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14790424.7A
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English (en)
French (fr)
Inventor
Nicolas WISNIACKI
Linda Burkly
Gerald Russell Galluppi
Ivan Alexandrov NESTOROV
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biogen MA Inc
Original Assignee
Biogen MA Inc
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Filing date
Publication date
Application filed by Biogen MA Inc filed Critical Biogen MA Inc
Publication of EP3052128A2 publication Critical patent/EP3052128A2/de
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2875—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/515—Complete light chain, i.e. VL + CL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]

Definitions

  • TWEAK is a proinflammatory cytokine belonging to the TNF ligand superfamily. TWEAK mediates its biological activity through its receptor Fnl4, which is expressed by different tissue cell types including mesenchymal, epithelial, and endothelial cells. TWEAK- Fnl4 signaling can lead to multiple cellular responses, including production of
  • TWEAK-Fnl4 pathway proinflammatory cytokines, chemokines, and matrix metalloproteinases.
  • Activation of the TWEAK-Fnl4 pathway is tightly regulated in vivo, where highly induced expression of TWEAK and Fnl4 occurs locally in the specific organs affected by tissue injury and inflammatory disease.
  • TWEAK acts on resident tissue cell types through its receptor Fnl4, mediating multiple cellular responses that contribute to pathological tissue damage and remodeling.
  • the method comprises administering a therapeutically effective amount of an anti-TWEAK (TNF-like weak inducer of apoptosis) antibody to a subject having or suspected of having lupus nephritis.
  • an anti-TWEAK TNF-like weak inducer of apoptosis
  • the therapeutically effective amount of the anti-TWEAK antibody is 20 mg kg. In some embodiments, the therapeutically effective amount of the anti-TWEAK antibody is 3 mg/kg.
  • the method for treating lupus nephritis comprises the step of administering a therapeutically effective amount of an anti-TWEAK antibody together with one or more non-TWEAK-related agents.
  • the non-TWEAK-related agent may be provided prior to, concurrently with, or after the anti-TWEAK antibody.
  • the subject may have been receiving the non-TWEAK related agent prior to receiving the anti-TWEAK antibody, and the subject may or may not continue to receive the same non-TWEAK-related agent after initiation of the anti-TWEAK antibody.
  • the non-TWEAK-related agent may be, for example, a steroid, such as prednisone, and/or an immunosuppressant such as mycophenolate mofetil (MMF).
  • administration of anti-TWEAK allows for example, a steroid, such as prednisone, and/or an immunosuppressant such as mycophenolate mofetil (MMF).
  • administration of anti-TWEAK allows for
  • administration of a reduced amount of the non-TWEAK-related agent can reduce the presence of side effects.
  • the method for treating lupus nephritis comprises the step of administering an anti-TWEAK antibody and a steroid to a subject having or suspected of having lupus nephritis. In some embodiments, the method for treating lupus nephritis comprises the step of administering an anti-TWEAK antibody and an immunosuppressant (e.g., MMF) to a subject having or suspected of having lupus nephritis.
  • an immunosuppressant e.g., MMF
  • the method for treating lupus nephritis comprises administering an anti- TWEAK antibody, a steroid, and an immunosuppressant (e.g., MMF) to a subject having or suspected of having lupus nephritis.
  • an immunosuppressant e.g., MMF
  • the method for treating lupus nephritis comprises
  • Methods for treating lupus nephritis comprising administering 20 mg/kg of an anti-TWEAK antibody described herein to a subject already receiving a steroid and an immunosuppressant (e.g., MMF) are also encompassed.
  • the subject may or may not continue to receive the steroid and/or an immunosuppressant (e.g., MMF) during treatment with the anti-TWEAK antibody.
  • the amount of the second agent administered can be decreased during or after treatment with anti-TWEAK antibody.
  • the method for treating lupus nephritis comprises
  • Methods for treating lupus nephritis comprising administering 3 mg/kg of an anti-TWEAK antibody described herein to a subject already receiving a steroid and an immunosuppressant (e.g., MMF) are also encompassed.
  • the subject may or may not continue to receive the steroid and/or an immunosuppressant (e.g., MMF) during treatment with the anti-TWEAK antibody.
  • the amount of the second agent administered can be decreased during or after treatment with anti-TWEAK antibody.
  • compositions for treating lupus nephritis are provided.
  • compositions comprising therapeutically effective amounts of an anti-TWEAK antibody are encompassed, as are compositions comprising an anti-TWEAK antibody and a steroid, an anti-TWEAK antibody and an immunosuppressant, and an anti-TWEAK antibody, a steroid, and an immunosuppressant.
  • compositions comprising an anti-TWEAK antibody and a steroid, an anti-TWEAK antibody and an immunosuppressant, and an anti-TWEAK antibody, a steroid, and an immunosuppressant.
  • the composition comprises an amount of antibody appropriate for administration of 20 mg/kg of an anti-TWEAK antibody, 3 mg/kg of an anti- TWEAK antibody, 20 mg/kg of an anti-TWEAK antibody and a steroid, 20 mg/kg of an anti- TWEAK antibody, a steroid, and an immunosuppressant (e.g., MMF), 3 mg/kg of an anti- TWEAK antibody and a steroid, or 3 mg/kg of an anti-TWEAK antibody, a steroid, and an immunosuppressant (e.g., MMF).
  • a composition comprising an amount of an anti-TWEAK antibody appropriate for administration of 20 mg/kg of the antibody optionally comprises a fixed dose of 1,600 mg of the antibody.
  • a composition comprising an amount of an anti- TWEAK antibody appropriate for administration of 3 mg/kg of the antibody optionally comprises a fixed dose of 240 mg of the antibody.
  • the compositions may be formulated for separate or concurrent administration.
  • the disclosure encompasses any of the compositions described herein for use in the treatment of lupus nephritis.
  • this disclosure provides methods and compositions for treating muscle atrophy.
  • the method involves administering a therapeutically effective amount of an anti-TWEAK antibody to subject having or suspected of having muscle atrophy.
  • the therapeutically effective amount of the anti- TWEAK antibody is 20 mg/kg.
  • the method for treating muscle atrophy comprises the step of administering a therapeutically effective amount of an anti-TWEAK antibody together with one or more non-TWEAK-related agents.
  • the non-TWEAK-related agent may be provided prior to, concurrently with, or after the anti-TWEAK antibody.
  • the subject may have been receiving the non-TWEAK related agent prior to receiving the anti-TWEAK antibody, and the subject may or may not continue to receive the same non-TWEAK-related agent after initiation of the anti-TWEAK antibody.
  • the non-TWEAK-related agent may be, for example, a branched amino acid such as leucine, isoleucine, valine, or lysine, as part of an amino acid therapy.
  • the non-TWEAK-related agent may be, for example, a selective androgen receptor modulator (SARM) such as tamoxifen, enobosarm, BMS-564,929, LGD-4033, AC-262,356, JNJ-28330835, LGD-2226, LGD-3303, S-40503, or S-23.
  • the non-TWEAK-related agent may be, for example, a low molecular weight heparin (LMWH) such as enoxaparin.
  • LMWH low molecular weight heparin
  • the non-TWEAK-related agent may be, for example, an agent that induces hypertrophy, such as a myostatin pathway inhibitor.
  • administration of anti-TWEAK allows for administration of a reduced amount of the non-TWEAK-related agent and can reduce the presence of side effects.
  • the method for treating muscle atrophy comprises the step of administering an anti-TWEAK antibody and an amino acid (e.g., leucine, isoleucine, valine, or lysine) to a human subject having or suspected of having muscle atrophy.
  • the method for treating muscle atrophy comprises the step of administering an anti-TWEAK antibody and a SARM to a human subject having or suspected of having muscle atrophy.
  • the method for treating muscle atrophy comprises the step of administering an anti-TWEAK antibody and a LMWH (e.g., enoxaparin) to a human subject having or suspected of having muscle atrophy.
  • LMWH e.g., enoxaparin
  • the method for treating muscle atrophy comprises the step of administering an anti-TWEAK antibody and an agent that induces hypertrophy (e.g., a myostatin pathway inhibitor) to a human subject having or suspected of having muscle atrophy.
  • the method for treating muscle atrophy comprises administering an anti-TWEAK antibody, an amino acid, a SARM and/or a LMWH to a human subject having or suspected of having muscle atrophy.
  • the human subject being treated for muscle atrophy has this condition as a result of a co-morbidity of a disease such as cancer, acquired
  • AIDS immunodeficiency syndrome
  • COPD chronic obstructive pulmonary disease
  • ALS amyotrophic lateral sclerosis
  • ALS amyotrophic lateral sclerosis
  • ALS amyotrophic lateral sclerosis
  • ALS amyotrophic lateral sclerosis
  • alcoholic myopathy inflammatory myopathy
  • glucocorticoid-induced myopathy osteoarthritis
  • rheumatoid arthritis spinal cord injury, stroke, inclusion body myositis, myotonic dystrophy, sarcopenia, diaphragm atrophy (e.g., resulting from intensive care unit stay), or other muscle atrophy resulting from intensive care unit stay.
  • the human subject being treated with an anti-TWEAK antibody or antigen binding fragment thereof has, is suspected of having, or is at risk of developing disuse muscle atrophy. In other embodiments, the human subject being treated with an anti-TWEAK antibody or antigen binding fragment thereof has, is suspected of having, or is at risk of developing neurogenic atrophy.
  • the human subject being treated with an anti-TWEAK antibody or antigen binding fragment thereof has or is at risk of developing muscle atrophy due to immobilization. In certain embodiments, the human subject being treated with an anti- TWEAK antibody or antigen binding fragment thereof has or is at risk of developing muscle atrophy due to malnutrition. In other embodiments, the human subject being treated with an anti-TWEAK antibody or antigen binding fragment thereof has or is at risk of developing muscle atrophy due to long-term corticosteroid therapy. In some embodiments, the human subject being treated with an anti-TWEAK antibody or antigen binding fragment thereof has or is at risk of developing muscle atrophy due to a burn.
  • the human subject being treated for muscle atrophy is administered an anti-TWEAK antibody or antigen-binding fragment thereof at a dose of 20 mg/kg every 4 weeks. In some embodiments, the human subject is administered a dose of 20 mg/kg every 3 weeks. In certain embodiments, the human subject is administered a dose of 20 mg/kg every 2 weeks. In one embodiments, the human subject is administered a dose of 20 mg/kg every week.
  • the human subject being treated for muscle atrophy is administered eight doses, seven doses, six doses, five doses, four doses, three doses, two doses, or one dose of an anti-TWEAK antibody or antigen-binding fragment thereof, wherein each dose is 20 mg/kg.
  • the human subject is administered the anti-TWEAK antibody or antigen-binding fragment thereof intravenously.
  • this disclosure provides a composition comprising an amount of antibody appropriate for administration of 20 mg/kg of an anti-TWEAK antibody and one or more of a SARM, a branched amino acid, a low molecular weight heparin, or an agent that induces hypertrophy (e.g., a myostatin pathway inhibitor).
  • a composition comprising an amount of an anti-TWEAK antibody appropriate for administration of 20 mg/kg of the antibody optionally comprises a fixed dose of 1,600 mg of the antibody.
  • the composition is a pharmaceutical composition that includes a
  • the anti-TWEAK antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence set forth in SEQ ID NO:4, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6 or 7; and a light chain variable domain (VL) CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1 1 or 12, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or 14, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15 or 16.
  • VH heavy chain variable domain
  • CDR complementarity determining region
  • VL light chain variable domain
  • the anti-TWEAK antibody or antigen-binding fragment thereof comprises a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3; and a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:8, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:9, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 10.
  • the anti-TWEAK antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 17, and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 18 or 19, or an antigen binding fragment thereof.
  • the anti-TWEAK antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:20, and a light chain comprising the amino acid sequence set forth in SEQ ID NO:21.
  • the method may further comprise evaluating the subject for levels of soluble TWEAK, or analyzing the results of a test that evaluated the subject for levels of soluble TWEAK.
  • the subject is administered any of the compositions described herein if the level of soluble TWEAK is increased as compared to a healthy control.
  • the evaluation includes contacting a biological sample of the subject, preferably a urine, serum, plasma, CSF or synovial fluid sample, with an agent that detects TWEAK, a TWEAK receptor (TWEAK-R) or a biomarker whose expression is modulated (e.g., increased) by TWEAK (e.g., in mesangial cells).
  • the method comprises analyzing the results of a test that evaluates the subject for levels of soluble TWEAK, and administering a therapeutically effective amount of an anti-TWEAK antibody to the patient if the levels of soluble TWEAK are determined to be increased compared to a healthy control.
  • the therapeutically effective amount of the anti-TWEAK antibody for treatment of lupus nephritis is selected from 20 mg/kg and 3 mg/kg. In this embodiment, the therapeutically effective amount of the anti-TWEAK antibody for treatment of muscle atrophy is 20 mg/kg.
  • all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the exemplary methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present application, including definitions, will control. The materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
  • Lupus nephritis remains a major cause of morbidity and mortality in SLE patients. Overt renal disease is found in at least one-third to one-half of SLE patients, with reports of 5-year renal survival with treatment ranging from 46-95%.
  • Class ITI Active lesions: focal proliferative l upus nephritis
  • Class III Active and chronic lesions: focal proliferative and sclerosing lupus nephritis
  • Class ⁇ Chronic inactive lesions with glomerular scars: focal sclerosing lupus nephritis
  • Ciass IV Diffuse lupus ephritis
  • This class is divided into diffuse segmental(iV-S) lupus nephritis when >50% of the involved glomeruli have segmental lesions, and diffuse global (IV-G) lupus nephritis when >50% of the involved glomeruli have global lesions. Segmental is comprised as a glomerular lesion that involves less than half of the glomerular tuft.
  • This class includes cases with diffuse wire loop deposits but with little or no glomerular proliferation
  • Class 1V-S Active lesions: diffuse segmental proliferative lupus nephritis
  • Class IV-G Active lesions: diffuse global proliferative lupus nephritis
  • Active and chronic lesions diffuse segmental proliferative and sclerosing lupus nephritis
  • Active and chronic lesions diffuse global proliferative and sclerosing lupus nephritis
  • Class IV-G Chronic inactive lesions with scars: diffuse global sclerosing lupus nephritis
  • Class V lupus nephritis may occur in combination with class ill or IV in which case both will be diagnosed
  • Physician would indicate and grades the proportion of glomeruli with fibrinoid necrosis and/or cellular crescents. In each physician would indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and fibrosis, severity of arteriosclerosis or other vascular lesions.
  • subjects meeting one or more of the criteria in Table 1 above are treated using the subject methods.
  • Specific patient populations are described in more detail below.
  • the human subject who has, or is suspected of having, LN has the following characteristics: 1) the subject has been diagnosed with SLE; 2) the subject has been diagnosed with ISN/RPS 2003 Class III or IV LN; and 3) the subject has proteinuria defined as urine protein/creatinine ratio (uPCR) greater than 1.0.
  • Subjects that meet these criteria may be administered therapeutically effective amounts of an anti-TWEAK antibody described herein, or therapeutically effective amounts of an anti-TWEAK antibody described herein in combination with a steroid and/or an immunosuppressant.
  • the human subject who has, or is suspected of having, LN has the following characteristics: 1) a biopsy-proven Class III or IV LN as classified by the ISN/RPS 2003; and 2) a uPCR greater than 1.
  • the human subject to be treated by the methods described herein has a diagnosis of SLE, and a soluble TWEAK level that is increased relative to a healthy control. Measurement of soluble TWEAK levels is described herein, and also in WO 2006/138219, at, for example, pages 4-6, and 36.
  • the human subject will not be treated according to the methods described herein if 12 or more weeks after diagnosis with LN, they have a greater than or equal to 30% increase in serum creatinine, optionally measured by two successive measurements separated by greater than or equal to 4 weeks, as compared to baseline, and have creatinine values outside normal range.
  • a diagnosis of SLE is made when at least four of the 1 1 criteria for classification of SLE are met. See, Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus
  • a diagnosis of SLE is made when at least four of the 1 1 criteria for classification of SLE are met, wherein at least one of the criteria is a positive antinuclear antibody (ANA), anti-SM, or anti-dsDNA antibody.
  • ANA positive antinuclear antibody
  • anti-SM anti-SM
  • anti-dsDNA antibody anti-dsDNA antibody
  • Hematologic Hemolytic anemia— with reticulocytosis
  • Immunologic Anti-DNA: antibody to native DNA in abnormal titer disorder
  • Anti-Sm presence of antibody to Sm nuclear antigen OR
  • a diagnosis of ISN/RPS 2003 Class III or IV LN is made according to Table 1, wherein the subject has either active or active/chronic disease, and wherein the diagnosis is confirmed by biopsy up to 3 months prior to diagnosis, and wherein the LN is active at diagnosis. Subjects are permitted to have co-existing Class V LN according to the ISN/RPS 2003 classification system.
  • Proteinuria and methods for measuring proteinuria are known to those of skill in the art.
  • proteinuria is expressed as a urine protein:creatinine ratio (uPCR). Renal function is often assessed by measuring the glomerular filtration rate (GFR), which describes the flow rate of filtered fluid through the kidney. GFR is often reported as an estimated GFR, or eGFR. See, e.g., Levey AS et al. (March 1999) Annals of Internal Medicine 130(6):461-70.
  • Skeletal muscle atrophy is defined as a progressive decrease in muscle mass that leads to weakness and impaired function. It occurs as a result of conditions of muscle disuse (e.g., immobilization, denervation, muscle unloading), aging, starvation, and a number of chronic disease states (e.g., chronic obstructive pulmonary disease and cancer). Regardless of the inciting event, skeletal muscle atrophy is characterized by a decrease in protein content, fiber diameter, force production, and endurance. Progressive loss of skeletal muscle mass may cause major physiological alterations. Muscle atrophy results in impaired functional strength, reduced insulin sensitivity, a decline in basal metabolic rate, and a concomitant increase in body fat mass.
  • the TWEAK-Fnl4 axis is as an important regulator of skeletal muscle wasting.
  • TWEAK-Fnl4 axis is a therapeutic strategy for prevention and/or treatment of conditions or diseases associated with muscle atrophy.
  • Skeletal muscle can atrophy in response to disuse, which may be secondary to conditions of nerve or blood supply deprivation and/or dug exposure such as glucocorticoids.
  • the human subject to be treated has or is suspected of having skeletal muscle atrophy resulting from muscle disuse.
  • the muscle disuse results from immobilization of a limb of the subject.
  • the human subject to be treated has skeletal muscle atrophy resulting from malnutrition.
  • the human subject to be treated has skeletal muscle atrophy resulting from long-term
  • the human subject to be treated has skeletal muscle atrophy resulting from burns. In certain embodiments, the human subject to be treated has skeletal muscle atrophy resulting from renal failure. In some embodiments, the human subject has, is suspected of having, or is at risk of developing neurogenic atrophy.
  • Skeletal muscle can also atrophy in conditions of genetic or degenerative disorders.
  • Muscular dystrophy constitutes a large group of hereditary myopathies characterized by atrophy and loss of muscle fibers in the absence of nerve disease; one common form that is included in this group is Duchenne's muscular dystrophy.
  • Congenital muscle disease may also occur in the context of glycogen storage diseases, such as acid maltase deficiency, which results in babies with weak muscles, poor athletes, enlarged hearts, and often early death from cardiac failure.
  • Congenital disorders leading to muscle atrophy also include, but are not limited to, mitochondrial myopathies, lipid myopathies, central tubular myopathies, and
  • skeletal muscle wasting also may occur as a component of neuronal disease, including but not limited to, amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • skeletal muscle wasting also known as cachexia, is an important pathological condition seen in most terminally ill cancer patients and often is directly responsible for patients' death.
  • Diseases of skeletal muscle that occur in the context of inflammation or autoimmunity include polymyositis, inflammatory myopathies, and glucocorticoid induced atrophy.
  • the human subject who has, or is suspected of having, or is at risk of developing muscle atrophy has a disease such as cancer, acquired immunodeficiency syndrome (AIDS), congestive heart failure, chronic obstructive pulmonary disease (COPD), renal failure, liver disease, cachexia, alcohol- associated myopathy, amyotrophic lateral sclerosis (ALS), dermatomyositis, polymyositis, Guillain-Barre syndrome, motor neuropathy, muscular dystrophy, glycogen storage disease, mitochondrial myopathy, lipid myopathy, central tubular myopathy, rhabdomyolysis, alcoholic myopathy, inflammatory myopathy, glucocorticoid-induced myopathy,
  • AIDS acquired immunodeficiency syndrome
  • COPD chronic obstructive pulmonary disease
  • ALS amyotrophic lateral sclerosis
  • ALS amyotrophic lateral sclerosis
  • dermatomyositis polymyositis
  • Guillain-Barre syndrome motor neuropathy
  • muscle atrophy results from a co-morbidity of one or more of these diseases.
  • the human subject to be treated by the methods described herein has a diagnosis of skeletal muscle atrophy, and a soluble TWEAK level that is increased relative to a healthy control. Measurement of soluble TWEAK levels is described herein, and also in
  • the anti-TWEAK antibody or antigen-binding fragment thereof comprises the six Complementarity Determining Regions (CDRs) from the murine and/or human P2D10 antibody disclosed in International Publication Number WO 2006/130374 at, for example, pages 1-13 and 44-48.
  • the anti-TWEAK antibody comprises/consists of the three heavy chain variable domain CDRs and the three light chain variable domain CDRs from a P2D10 antibody. Accordingly, the anti-TWEAK antibody may include all three of the P2D10 heavy chain variable domain CDRs, which are as follows:
  • CDR1 GFTFSRYAMS (SEQ ID NO: l)
  • CDR2 EIS SGGS YPYYPDTVTG (SEQ ID NO:2), and
  • CDR3 VLYYDYDGDRIEVMDY (SEQ ID NO:3),
  • CDR1 RSSQSLVSSKGNTYLH (SEQ ID NO:8)
  • CDR2 KVSNRFS (SEQ ID NO:9), and
  • CDR3 SQSTHFPRT (SEQ ID NO: 10).
  • CDRs refer to CDRs as defined by Chothia's hypervariable loops.
  • the anti-TWEAK antibody includes a heavy chain variable domain comprising each of SEQ ID NOs: 1, 2, and 3.
  • the anti-TWEAK antibody includes a light chain variable domain comprising each of SEQ ID NOs:8, 9, and 10.
  • the anti-TWEAK antibody includes a P2D10 heavy chain variable domain comprising the following sequence:
  • the antibody includes a P2D10 light chain variable domain comprising the following sequence: DWMTQSPLSLPVTPGEPASISCRSSQSLVSSKGNTYLHWYLQKPGQSPQ
  • the antibody includes a P2D10 light chain variable domain comprising the following sequence:
  • the anti-TWEAK antibody has a heavy chain variable domain comprising SEQ ID NO: 17 and light chain variable domain comprising SEQ ID NO: 18. In some embodiments, the anti-TWEAK antibody has a heavy chain variable domain comprising SEQ ID NO: 17 and light chain variable domain comprising SEQ ID NO: 19.
  • the anti-TWEAK antibody has a heavy chain variable domain consisting, or consisting essentially of, SEQ ID NO: 17, and light chain variable domain consisting, or consisting essentially of, SEQ ID NO: 18 or SEQ ID NO: 19. In some embodiments, the anti-TWEAK antibody has a heavy chain variable domain consisting of SEQ ID NO: 17 and light chain variable domain consisting of SEQ ID NO: 18 or SEQ ID NO: 19.
  • the heavy chain variable domain of the anti-TWEAK antibody includes an amino acid sequence which is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or more identical to SEQ ID NO: 17 or which differs at least at 1 to 5 residues, but at fewer than 40, 30, 20, or 10 residues, from SEQ ID NO: 17.
  • the light chain variable domain of the anti-TWEAK antibody includes an amino acid sequence which is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or more identical to SEQ ID NO: 18 or which differs at least at 1 to 5 residues, but at fewer than 40, 30, 20, or 10 residues, from SEQ ID NO: 18.
  • the light chain variable domain of the anti-TWEAK antibody includes an amino acid sequence which is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or more identical to SEQ ID NO: 19 or which differs at least at 1 or 5 residues, but at fewer than 40, 30, 20, or 10 residues, from SEQ ID NO: 19
  • the anti-TWEAK antibody is an antibody of the IgG 1 isotype.
  • the anti-TWEAK antibody includes a full-length P2D10 heavy chain comprising the following sequence:
  • the anti-TWEAK antibody includes a full-length P2D10 light chain comprising the following sequence:
  • DVVMTQSPLSLPVTPG EPASISCRSSQSLVSSKGNTYLHWYLQKPGQSPQFLIYKVSNRF SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHFPRTFGGGTKVEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 21)
  • the anti-TWEAK antibody includes a full-length P2D10 light chain comprising the following sequence: DVVMTQS PLS LPVT PGEPAS I SCRS SQSLVS SKGNTYLHWYLQKPGQS PQLL IYKVSNRF
  • the anti-TWEAK antibody has a heavy chain comprising SEQ ID NO:20 and light chain comprising SEQ ID NO:21. In some embodiments, the anti- TWEAK antibody has a heavy chain comprising SEQ ID NO:20 and light chain comprising SEQ ID NO:22.
  • the anti-TWEAK antibody has a heavy chain consisting of
  • the anti- TWEAK antibody has a heavy chain consisting of SEQ ID NO:20 and light chain consisting of SEQ ID NO:22.
  • the heavy chain of the anti-TWEAK antibody includes an amino acid sequence which is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or more identical to SEQ ID NO:20 or which differs at least at 1 to 5 residues, but at fewer than 40, 30, 20, or 10 residues, from SEQ ID NO:20.
  • the light chain of the anti-TWEAK antibody includes an amino acid sequence which is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or more identical to SEQ ID NO:21 or which differs at least at 1 to 5 residues, but at fewer than 40, 30, 20, or 10 residues, from SEQ ID NO:21.
  • the light chain of the anti-TWEAK antibody includes an amino acid sequence which is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or more identical to SEQ ID NO:22 or which differs at least at 1 to 5 residues, but at fewer than 40, 30, 20, or 10 residues, from SEQ ID NO:22.
  • the anti-TWEAK antibody comprises, in the heavy chain variable domain, at least one, two, or three of SEQ ID NOs: 1, 2, and 3.
  • the heavy chain variable domain sequence may comprise SEQ ID NO:3.
  • the heavy chain variable domain may include two of the sequences, e.g., it includes SEQ ID NOs: l and 3, or it includes SEQ ID NOs:2 and 3.
  • the anti-TWEAK antibody comprises, in the light chain variable domain, at least one, two, or three of SEQ ID NOs: 8, 9, and 10.
  • the light chain variable domain sequence may comprise SEQ ID NO: 10.
  • the light chain variable domain may include two of the sequences, e.g., it includes SEQ ID NOs 8 and 10, or it includes SEQ ID NOs:9 and 10.
  • the anti-TWEAK antibody includes, in the heavy chain variable domain sequence, at least one, two, or three of the following sequences within a CDR:
  • the anti-TWEAK antibody includes, in the light chain variable domain sequence, at least one, two, or three of the following sequences within a CDR region:
  • the anti-TWEAK antibody includes a heavy chain variable domain comprising the sequence of each of SEQ ID NOs: l, 2, and 3, wherein each sequence contains from zero to four modifications (e.g., substitutions, insertions or deletions) per CDR.
  • the anti-TWEAK antibody includes a light chain variable domain comprising the sequence of each of SEQ ID NOs:8, 9, and 10, wherein each sequence contains from zero to four modifications (e.g., substitutions, insertions or deletions) per CDR.
  • the antibody can be a human, humanized, CDR-grafted, chimeric, mutated, affinity matured, deimmunized, synthetic or otherwise in /rogenerated antibody, and combinations thereof.
  • the anti-TWEAK antibody is a humanized antibody.
  • the anti-TWEAK antibody may be a CDR-grafted antibody comprising the CDRs of the mouse P2D10 antibody described in International Publication Number WO
  • 2006/130374 i.e., SEQ ID NOs: l, 2, and 3, and SEQ ID NOs:8, 9, and 10 for light chain CDRs
  • grafted into human heavy and light chain variable domains to create an antibody with mouse P2D10 CDRs and human framework regions in the variable domain.
  • the heavy chain framework (e.g., FR1, FR2, FR3, individually, or a sequence encompassing FR1, FR2, and FR3, but excluding CDRs) includes an amino acid sequence which is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or more identical to the heavy chain framework of one of the following germline V segment sequences: DP-25, DP-1, DP-12, DP-9, DP-7, DP-31, DP-32, DP-33, DP-58, DP-54, other VH I subgroup germline sequence, other VH III subgroup germline sequence, or another V gene which is compatible with the canonical structure class 1-3 (see, e.g., Chothia et al.
  • frameworks compatible with the canonical structure class 1-3 include frameworks with the one or more of the following residues according to Kabat numbering: Ala, Gly, Thr, or Val at position 26; Gly at position 26; Tyr, Phe, or Gly at position 27; Phe, Val, He, or Leu at position 29; Met, He, Leu, Val, Thr, Trp, or He at position 34; Arg, Thr, Ala, Lys at position 94; Gly, Ser, Asn, or Asp at position 54; and Arg at position 71.
  • the light chain framework (e.g., FR1 , FR2, FR3, individually, or a sequence encompassing FR1, FR2, and FR3, but excluding CDRs) includes an amino acid sequence, which is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or more identical to the light chain framework of a VKII subgroup germline sequence or one of the following germline V segment sequences: A17, Al, A18, A2, A19/A3, A23, a VKI subgroup germline sequence (e.g., a DPK9 sequence), or another V gene which is compatible with the canonical structure class 4-1 (see, e.g., Tomlinson et al.
  • frameworks compatible with the canonical structure class 4- 1 include frameworks with the one or more of the following residues according to Kabat numbering: Val or Leu or He at position 2; Ser or Pro at position 25; He or Leu at position 27b; Gly at position 29; Phe or Leu at position 33; and Phe at position 71. Further, according to the Kabat numbering, position 48 can be He or Val.
  • the light chain framework (e.g., FR1, FR2, FR3, individually, or a sequence encompassing FR1, FR2, and FR3, but excluding CDRs) includes an amino acid sequence, which is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or more identical to the light chain framework of a VKI subgroup germline sequence, e.g., a DPK9 sequence.
  • the light or the heavy chain variable framework (e.g., the region encompassing at least FR1, FR2, FR3, and optionally FR4) can be chosen from: (a) a light or heavy chain variable framework including at least 80%, 90%, 95%, or preferably 100% of the amino acid residues from a human light or heavy chain variable framework, e.g., a light or heavy chain variable framework residue from a human mature antibody, a human germline sequence, a human consensus sequence, or a human antibody described herein; (b) a light or heavy chain variable framework including from 20% to 80%, 40% to 60%, 60% to 90%, or 70% to 95% of the amino acid residues from a human light or heavy chain variable framework, e.g., a light or heavy chain variable framework residue from a human mature antibody, a human germline sequence, a human consensus sequence; (c) a non-human framework (e.g., a rodent framework); or (d) a non-human framework that has been modified, e.g., a
  • the heavy chain variable domain sequence includes human residues or human consensus sequence residues at one or more of the following positions (preferably at least five, ten, twelve, or all): (in the FR of the variable domain of the light chain) 4L, 35L, 36L, 38L, 43L, 44L, 58L, 46L, 62L, 63L, 64L, 65L, 66L, 67L, 68L, 69L, 70L, 71L, 73L, 85L, 87L, 98L, and/or (in the FR of the variable domain of the heavy chain) 2H, 4H, 24H, 36H, 37H, 39H, 43H, 45H, 49H, 58H, 60H, 67H, 68H, 69H, 70H, 73H, 74H, 75H, 78H, 91H, 92H, 93H, and/or 103H (according to the Kabat numbering).
  • the anti-TWEAK antibody includes at least one non-human CDR, e.g., a murine CDR, e.g., a CDR from the P2D 10 antibody as described in International Publication Number WO 2006/130374, or a variant thereof, and at least one framework which differs from a framework of P2D10 by at least one amino acid, e.g., at least 5, 8, 10, 12, 15, or 18 amino acids.
  • the anti-TWEAK antibody may include one, two, three, four, five, or six such non-human CDRs and include at least one amino acid difference in at least three of HC FR1, HC FR2, HC FR3, LC FR1, LC FR2, and LC FR3.
  • variable domains include amino acid positions in the framework region that are variously derived from both a murine antibody (e.g., P2D10) and a humanized antibody (e.g., 56-84m and K107) or germline sequence.
  • the variable domain will include a number of positions at which the amino acid is identical to both the murine P2D10 antibody and the human antibody (or germline sequence) because the two are identical at that position.
  • at least 50, 60, 70, 80, or 90% of the positions of the variable domain are preferably identical to the human antibody (or germline sequence) rather than the murine.
  • none, or at least one, two, three, or four of such remaining framework positions may be identical to the murine P2D10 antibody rather than to the human antibody.
  • one or two such positions can be murine; in HC FR2, one or two such positions can be murine; in FR3, one, two, three, or four such positions can be murine; in LC FR1, one, two, three, or four such positions can be murine; in LC FR2, one or two such positions can be murine; in LC FR3, one or two such positions can be murine.
  • the heavy and light chains of the anti-TWEAK antibody can be full-length or substantially full-length.
  • the protein can include at least one, and preferably two, complete heavy chains, and at least one, and preferably two, complete light chains.
  • the antibody can include an antigen-binding fragment (e.g., a Fab, F(ab')2, Fv or a single chain Fv fragment.
  • the antibody has a heavy chain constant region chosen from, e.g., IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE; particularly, chosen from, e.g., IgGl, IgG2, IgG3, and IgG4, more particularly, IgGl (e.g., human IgGl).
  • the heavy chain constant region is human or a modified form of a human constant region.
  • the antibody has a light chain constant region chosen from, e.g., a kappa or lambda light chain, particularly kappa light chain (e.g., human kappa).
  • the constant region of an anti-TWEAK antibody may be modified by mutation of one or more amino acid residues to impart a desired functional property (e.g., altered effector function or half-life) using methods well known in the art.
  • the non-TWEAK-related agents described herein for use in treatment of lupus nephritis may be a steroid, including corticosteroids and gluco-corticosteroids.
  • the steroid may be selected from prednisone, prednisolone, methylprednisolone, hydrocortisone, and dexamethasone.
  • Other steroids are well known and encompassed in the methods and compositions described herein.
  • the steroid is provided orally or intravenously.
  • the steroid is provided at a low dose, e.g., less than 10 mg/day, e.g., less than 7.5 mg per day.
  • the steroid is provided at a medium dose, e.g., between 7.5 and 15 mg per day.
  • the steroid is provided at a high dose, e.g., greater than 15 mg per day.
  • the non-TWEAK-related agent for use in treatment of lupus nephritis may also be an immunosuppressant.
  • the immunosuppressant may be selected from mycophenolate mofetil (MMF), cyclophosphamide, azathioprine, and cyclosporine. Other immunosuppressants are well known and are encompassed in the methods described herein.
  • the immunosuppressant is provided at a low, intermediate, or high dose. Low, intermediate, and high doses will vary between immunosuppressants, and will be known to the skilled artisan.
  • the immunosuppressant is MMF.
  • a low dose of MMF is less than or equal to 500 mg
  • an intermediate dose is greater than 500 mg and less than or equal to 3 grams
  • a high dose is greater than 3 grams.
  • the non-TWEAK-related agent for use in treatment of muscle atrophy can be a branched amino acid (e.g., leucine, isoleucine, valine, or lysine).
  • SARM selective androgen receptor modulator
  • SARMs include tamoxifen, enobosarm, BMS-564,929, LGD-4033, AC-262,356, JNJ-28330835, LGD-2226, LGD-3303, S-40503, and S-23.
  • LMWH low molecular weight heparin
  • Enoxaparin is an exemplary LMWH.
  • Another non-TWEAK-related agent for use in treatment of muscle atrophy can be an agent that induces hypertrophy, such as a myostatin pathway inhibitor.
  • the anti-TWEAK antibody may be administered in combination with one or more non-TWEAK-related agents.
  • the anti-TWEAK antibody and one or more additional agents are administered to a subject at the same time or within a certain interval of one another, such that there is overlap of an effect of each agent on the patient.
  • the administrations of the anti-TWEAK antibody and the additional agent or agents are spaced sufficiently close together such that a combinatorial effect is achieved.
  • the interval can be an interval of hours, days, or weeks.
  • the agents are concurrently bioavailable in the subject, i.e., the agents may each be detected in the subject at the same time.
  • at least one administration of one of the agents, e.g., the anti-TWEAK antibody is made while a second agent is still present at a therapeutic level in the subject.
  • the anti-TWEAK antibody is administered between an earlier and a later administration of an additional agent.
  • an additional agent is administered between an earlier and a later administration of the anti-TWEAK antibody.
  • at least one administration of one of the agents, e.g., the anti- TWEAK antibody is made within 1, 7, 14, 30, or 60 days of the additional agent.
  • the subject prior to administering the anti-TWEAK antibody and one or more additional agents, the subject was receiving a non-TWEAK related agent.
  • the subject may have had a response that did not meet a predetermined threshold.
  • the subject can be one who has not been previously administered either an anti-TWEAK antibody or a non-TWEAK-related agent prior to being administered the anti-TWEAK antibody and a non-TWEAK-related agent in combination.
  • the anti-TWEAK antibody and one or more non-TWEAK related agents are provided as a co-formulation, and the co-formulation is administered to the subject. It is further possible, e.g., at least 24 hours before or after administering the co- formulation, to administer one of the agents separately from the other.
  • the anti-TWEAK antibody and one or more non-TWEAK related agents are provided as separate formulations, and the step of administering includes sequentially administering the agents. The sequential administrations can be provided on the same day (e.g., within one hour of one another or at least 3, 6, or 12 hours apart) or on different days.
  • the anti-TWEAK antibody and the one or more non-TWEAK related agents may each be administered as a plurality of doses separated in time, e.g., according to a regimen.
  • the regimen for one or both may have a regular periodicity.
  • the regimen for an additional agent can have a different periodicity from the regimen for the anti-TWEAK antibody, e.g., one can be administered more frequently than the other.
  • the agents can be administered by any appropriate method, e.g., subcutaneous ly, intramuscularly, or intravenously.
  • the subject can be administered doses of an additional agent and doses of the anti-TWEAK antibody for greater than 14 weeks, greater than six or nine months, greater than 1, 1.5, or 2 years.
  • the anti-TWEAK antibody and one or more non-TWEAK related agent is administered at about the same dose as the dose used for monotherapy.
  • the non-TWEAK related agent is administered at a dosage that is equal to or less than an amount required for efficacy if administered alone (e.g., at least 10, 20, 30, or 40% less).
  • the subject is administered a reduced dose of that non- TWEAK related therapy after receiving the anti-TWEAK antibody (relative to the dose of the non-TWEAK related therapy received before receiving the anti-TWEAK antibody for the first time).
  • a subject can be evaluated after receiving the first and second agent, e.g., for indicia of responsiveness.
  • a skilled artisan can use various clinical or other indicia of effectiveness of treatment.
  • the subject can be monitored at various times during a regimen.
  • an anti-TWEAK antibody as described herein and a non-TWEAK-related agent may be administered in the same or separate pharmaceutical compositions which comprise a "therapeutically effective amount" of an anti-TWEAK antibody and/or a "therapeutically effective amount” of one or more non-TWEAK related agents.
  • the therapeutically effective amount of the anti-TWEAK antibody for treatment of lupus nephritis or muscle atrophy is 20 mg/kg.
  • the therapeutically effective amount of the anti-TWEAK antibody for treatment of lupus nephritis is 3 mg/kg.
  • a subject is said to be successfully treated (i.e., to have received a "therapeutically effective amount" of an agent or combination of agents) when there is a complete renal response, characterized by urinary protein: creatine ratio (uPCR) less than 0.5 with greater than or equal to 50% reduction of uPCR from baseline (i.e., the uPCR of the subject prior to treatment with an anti-TWEAK antibody or the uPCR of a healthy control) and estimated eGFR within normal range.
  • uPCR urinary protein: creatine ratio
  • a subject is said to be successfully treated when there is a partial renal response characterized by a greater than or equal to 50% reduction in uPCR from baseline with one of the following: a) uPCR of less than 1.0 if the day 1 (baseline) was greater than or equal to 3.0, or b) uPCR greater than 3.0 if the Day 1 (baseline) ratio was greater than 3.0; and stabilization of renal function (eGFR plus or minus 25% of day 1 (baseline) or serum creatinine within normal range.
  • the following are exemplary methods that can be used to determine if a human subject has been successfully treated with an anti-TWEAK antibody therapy (either alone or in combination with other agent(s)).
  • a subject is said to be successfully treated when there is a change in the magnitude of muscle atrophy at least one, or at least two, months after start of treatment.
  • the percentage change in the magnitude of muscle atrophy can be determined by, e.g., Tl-weighted magnetic resonance imaging (T1W-MRI) analysis of the cross-sectional area of the muscle under examination.
  • a subject is said to be successfully treated when there is an improvement in isometric knee-extension strength and/or isometric plantar- flexion strength as measured by e.g., dynamometry.
  • a subject is said to be successfully treated when there is a change in total cross-sectional area of type I and type II muscle fibers as measured by histological analysis of muscle biopsy.
  • a subject is said to be successfully treated when there is a change in recovery of muscle oxidative metabolism as measured by, e.g., near-infrared spectroscopy of the muscle being treated.
  • a subject is said to be successfully treated when there is a change in biomarkers related to muscle atrophy compared to baseline or different time points during treatment.
  • biomarkers include, but are not limited to, follistatin, myostatin, and C-terminal agrin fragment (CAF).
  • a subject is said to be successfully treated when the subject is determined by a health care practitioner to improve compared with baseline (day of or the day before treatment commences) in timed functional activity performance such as by the five times sit-to-stand test (FTSST), the timed-up-and-go(TUG) test, and the stair climbing test (SCT).
  • FTSST sit-to-stand test
  • TSG timed-up-and-go
  • SCT stair climbing test
  • Such techniques can include detecting the presence, levels, expression or activity of a TWEAK, e.g., by qualitative or quantitative analysis of mR A, cDNA, or protein, or by evaluating one or more nucleotides in a nucleic acid (genomic, mRNA, or cDNA) encoding TWEAK or TWEAK-R.
  • Such techniques include methods for protein detection (e.g., Western blot or ELISA), and hybridization-based methods for nucleic acid detection (e.g., PCR or Northern blot).
  • an immunoassay can be used to detect TWEAK protein, e.g., in a urine sample of the subject.
  • the method can include administering a labeled TWEAK or TWEAK-R binding agent (e.g., an antibody) to a subject, and evaluating localization of the labeled binding agent in the subject, e.g., by imaging the subject (e.g., imaging at least a portion of the kidney of the subject).
  • the expression level of a TWEAK can be determined using an antibody specific for TWEAK (e.g., using a western blot or an ELISA assay).
  • An anti-TWEAK antibody can be formulated as a pharmaceutical composition, e.g., for administration to a subject to treat lupus nephritis.
  • a pharmaceutical composition includes a pharmaceutically acceptable carrier.
  • composition includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the composition can include a pharmaceutically acceptable salt, e.g., an acid addition salt or a base addition salt (see e.g., Berge, S.M., et al. (1977) J. Pharm. Sci. 66: 1-19).
  • a pharmaceutically acceptable salt e.g., an acid addition salt or a base addition salt (see e.g., Berge, S.M., et al. (1977) J. Pharm. Sci. 66: 1-19).
  • the anti-TWEAK antibody can be formulated according to standard methods.
  • the anti-TWEAK antibody can be formulated with excipient materials, such as sodium chloride, sodium dibasic phosphate heptahydrate, sodium monobasic phosphate, and a stabilizer. It can be provided, for example, in a buffered solution at a suitable concentration and can be stored at 2-8°C.
  • excipient materials such as sodium chloride, sodium dibasic phosphate heptahydrate, sodium monobasic phosphate, and a stabilizer. It can be provided, for example, in a buffered solution at a suitable concentration and can be stored at 2-8°C.
  • compositions may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
  • the preferred form can depend on the intended mode of administration and therapeutic application.
  • compositions for the agents described herein are in the form of injectable or infusible solutions.
  • the anti-TWEAK antibody is supplied as a sterile liquid drug product at a concentration of lOOmg/mL in sodium succinate (pH 5.5), succinic acid, L- arginine, and polysorbate 80.
  • the anti-TWEAK antibody is provided in 3 mL vials containing 1 mL of lOOmg/mL anti-TWEAK antibody.
  • the anti-TWEAK antibody is provided in composition containing a fixed dose of 1,600 mg or 240 mg of an anti-TWEAK antibody and a pharmaceutically acceptable carrier.
  • compositions can be administered by a parenteral mode (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection).
  • parenteral administration e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection.
  • parenteral administration e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection.
  • parenteral administration e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection.
  • parenteral administration e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection.
  • composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable for stable storage at high concentration.
  • Sterile injectable solutions can be prepared by incorporating an agent described herein in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating an agent described herein into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying that yields a powder of an agent described herein plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
  • the anti-TWEAK antibody may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, and microencapsulated delivery systems.
  • a controlled release formulation including implants, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
  • An anti-TWEAK antibody can be modified, e.g., with a moiety that improves its stabilization and/or retention in circulation, e.g., in blood, serum, or other tissues, e.g., by at least 1.5, 2, 5, 10, or 50 fold.
  • the modified blocking agent can be evaluated to assess whether it can reach sites of damage after a stroke (e.g., by using a labeled form of the blocking agent).
  • the anti-TWEAK antibody can be associated with a polymer, e.g., a substantially non-antigenic polymer, such as a polyalkylene oxide or a polyethylene oxide.
  • a polymer e.g., a substantially non-antigenic polymer, such as a polyalkylene oxide or a polyethylene oxide.
  • Suitable polymers will vary substantially by weight. Polymers having molecular number average weights ranging from about 200 to about 35,000 Daltons (or about 1,000 to about 15,000, and 2,000 to about 12,500) can be used.
  • an anti-TWEAK antibody can be conjugated to a water-soluble polymer, e.g., a hydrophilic polyvinyl polymer, e.g. polyvinylalcohol or
  • polyvinylpyrrolidone A non-limiting list of such polymers include polyalkylene oxide homopolymers such as polyethylene glycol (PEG) or polypropylene glycols,
  • polyoxyethylenated polyols such as polyoxyethylenated polyols, copolymers thereof and block copolymers thereof, provided that the water solubility of the block copolymers is maintained.
  • Additional useful polymers include polyoxyalkylenes such as polyoxyethylene, polyoxypropylene, and block copolymers of polyoxyethylene and polyoxypropylene (Pluronics); polymethacrylates; carbomers; and branched or unbranched polysaccharides.
  • the two agents can be formulated separately or together.
  • the respective pharmaceutical compositions can be mixed, e.g., just prior to administration, and administered together or can be administered separately, e.g., at the same or different times.
  • the anti-TWEAK antibody can be administered to a subject, e.g., a human subject, by a variety of methods.
  • the route of administration is one of:
  • IV intravenous injection or infusion
  • SC subcutaneous injection
  • IP intraperitoneally
  • IMV intracerebroventricular
  • the anti-TWEAK agent can be administered as a fixed dose (i.e., independent of the weight of the patient), or in a mg/kg dose (i.e., a dose which varies based on the weight of the subject).
  • the dosage of the anti-TWEAK antibody is 20 mg/kg. In another embodiment, for treating lupus nephritis, the dosage of the anti-TWEAK antibody is 3 mg/kg. Fixed doses corresponding to these concentrations may also be prepared.
  • the route and/or mode of administration of the anti-TWEAK antibody can also be tailored for the individual case, e.g., by monitoring the subject, e.g., using assessment criteria discussed herein.
  • the dose may be administered every 2 months, every 6 weeks, monthly, biweekly, weekly, or daily, as appropriate, over a period of time to encompass at least 2 doses, 3 doses, 5 doses, 10 doses, or more.
  • Dosage unit form or "fixed dose” as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier and optionally in association with the other agent. Single or multiple dosages may be given. Alternatively, or in addition, the blocking agent may be administered via continuous infusion. The treatment can continue for days, weeks, months or even years.
  • a pharmaceutical composition may include a "therapeutically effective amount" of an agent described herein. Such effective amounts can be determined based on the effect of the administered agent, or the combinatorial effect of agents if more than one agent is used. A therapeutically effective amount of an agent may also vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic, or detrimental effects, of the composition is outweighed by the therapeutically beneficial effects. In one embodiment, the therapeutically effective amount of the anti- TWEAK antibody is 20 mg/kg. In another embodiment, the therapeutically effective amount of the anti-TWEAK antibody is 3 mg/kg.
  • subjects having or suspected of having lupus nephritis that are currently being administered a steroid and an immunosuppressant according to the standard of care are administered 20 mg/kg or 3 mg/kg of the anti-TWEAK antibody described herein.
  • the anti-TWEAK antibody is administered parenterally every four weeks for at least 48 weeks.
  • the steroid e.g. prednisone
  • the steroid is administered at a low dose, e.g., less than 7.5 mg/day. In one embodiment, this represents a reduction in the amount of steroid that the patient previously received.
  • the steroid e.g. prednisone
  • immunosuppressant e.g., MMF
  • a low dose e.g., less than or equal to 500 grams. In one embodiment, this represents a reduction in the amount of
  • the subject that is currently being administered prednisone and an immunosuppressant continues to receive the steroid and an immunosuppressant (e.g., MMF) throughout treatment with the anti-TWEAK antibody, so that the anti-TWEAK antibody is considered to be an "add-on" treatment to background therapy.
  • an immunosuppressant e.g., MMF
  • subjects having or suspected of having muscle atrophy are administered 20 mg/kg of the anti-TWEAK antibody described herein.
  • the anti-TWEAK antibody is administered intravenously in 4 single doses of 20 mg/kg at two, three or four week intervals.
  • the subject's limbs are immobilized (e.g., in a brace)
  • the subject is also administered enoxaparin (40 mg QD) by subcutaneous injection during the immobilization period.
  • compositions that comprise the anti-TWEAK antibody alone or in combination with non-TWEAK related agent(s) can be administered with a medical device.
  • the device can be designed with features such as portability, room temperature storage, and ease of use so that it can be used in emergency situations, e.g., by an untrained subject or by emergency personnel in the field, removed to medical facilities and other medical equipment.
  • the device can include, e.g., one or more housings for storing pharmaceutical preparations that include anti-TWEAK antibody, and can be configured to deliver one or more unit doses of the blocking agent.
  • the pharmaceutical composition can be administered with a needleless hypodermic injection device, such as the devices disclosed in US 5,399, 163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556.
  • a needleless hypodermic injection device such as the devices disclosed in US 5,399, 163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556.
  • implants and modules examples include: US 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; US 4,486,194, which discloses a therapeutic device for administering medicaments through the skin; US 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; US 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; US 4,439, 196, which discloses an osmotic drug delivery system having multi- chamber compartments; and US 4,475,196, which discloses an osmotic drug delivery system. Many other devices, implants, delivery systems, and modules are also known.
  • kits An anti-TWEAK antibody alone or in combination with non-TWEAK related agents can be provided in a kit.
  • the kit includes (a) a container that contains a composition that includes an anti-TWEAK antibody alone or in combination with one or more non-TWEAK related agents, and optionally (b) informational material.
  • the informational material can be descriptive, instructional, marketing or other material that relates to the methods described herein and/or the use of the agents for therapeutic benefit.
  • the kit may also comprise a first container that contains a composition that includes the anti- TWEAK antibody, and a second container that includes a non-TWEAK-related agent or agents.
  • the composition in the kit can include other ingredients, such as a solvent or buffer, a stabilizer, or a preservative.
  • the blocking agent can be provided in any form, e.g., liquid, dried or lyophilized form, preferably substantially pure and/or sterile.
  • the liquid solution preferably is an aqueous solution.
  • reconstitution generally is by the addition of a suitable solvent.
  • the solvent e.g., sterile water or buffer, can optionally be provided in the kit.
  • the kit can include one or more containers for the composition or compositions containing the agents.
  • the kit contains separate containers, dividers or compartments for the composition and informational material.
  • the composition can be contained in a bottle, vial, or syringe, and the informational material can be contained in a plastic sleeve or packet.
  • the separate elements of the kit are contained within a single, undivided container.
  • the composition is contained in a bottle, vial or syringe that has attached thereto the informational material in the form of a label.
  • the kit includes a plurality (e.g., a pack) of individual containers, each containing one or more unit dosage forms (e.g., a dosage form described herein) of the agents.
  • the containers can include a combination unit dosage, e.g., a unit that includes both the anti-TWEAK antibody and the second agent, e.g., in a desired ratio.
  • the kit includes a plurality of syringes, ampules, foil packets, blister packs, or medical devices, e.g., each containing a single combination unit dose.
  • the containers of the kits can be air tight, waterproof (e.g., impermeable to changes in moisture or evaporation), and/or light-tight.
  • the kit optionally includes a device suitable for administration of the composition, e.g., a syringe or other suitable delivery device.
  • a device suitable for administration of the composition e.g., a syringe or other suitable delivery device.
  • the device can be provided pre-loaded with one or both of the agents or can be empty, but suitable for loading.
  • a commercial package can be prepared comprising a combination described herein together with instructions for simultaneous, separate or sequential use.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
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  • Engineering & Computer Science (AREA)
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  • Epidemiology (AREA)
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  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP14790424.7A 2013-10-04 2014-10-03 Tweak-antagonisten zur behandlung von lupus nephritis und muskelatrophie Withdrawn EP3052128A2 (de)

Applications Claiming Priority (2)

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US201361887209P 2013-10-04 2013-10-04
PCT/US2014/059007 WO2015051234A2 (en) 2013-10-04 2014-10-03 Tweak antagonists for treating lupus nephritis and muscle atrophy

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EP3052128A2 true EP3052128A2 (de) 2016-08-10

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CA2597945C (en) 2005-02-17 2016-07-12 Biogen Idec Ma Inc. Treating neurological disorders
WO2006138219A2 (en) 2005-06-13 2006-12-28 Biogen Idec Ma Inc. Methods of diagnosis / prognosis of inflammatory conditions

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US4447233A (en) 1981-04-10 1984-05-08 Parker-Hannifin Corporation Medication infusion pump
US4439196A (en) 1982-03-18 1984-03-27 Merck & Co., Inc. Osmotic drug delivery system
US4447224A (en) 1982-09-20 1984-05-08 Infusaid Corporation Variable flow implantable infusion apparatus
US4487603A (en) 1982-11-26 1984-12-11 Cordis Corporation Implantable microinfusion pump system
US4486194A (en) 1983-06-08 1984-12-04 James Ferrara Therapeutic device for administering medicaments through the skin
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